Physiologically active organic compounds have greatly varying physiological activities depending on their optical isomers. In some cases, they exhibit activities entirely opposite to expectation. Therefore, it is an important subject to efficiently and exclusively synthesize only useful optical isomers.
Isoquinoline type alkaloids are a series of physiologically active substances obtained from naturally-occurring materials and are widely employed as pharmaceuticals. In particular, benzylisoquinoline type compounds are not only important per se but also useful as intermediates for introducing into various other physiologically active substances such as morphine. Several processes are known for obtaining the benzylisoquinoline type compounds as optically active isomers. For example, tetrahydropapaverine is synthesized by forming its racemate, for example, by reduction of papaverine as described in, e.g., W. Awe et al., Ber. 70, 472 (1937) or addition of a benzyl group to tetrahydroisoquinoline as described, e.g., in T. Shono et al., Tetrahedron Letter, Vol. 22, No. 25, 2385 (1981) and then optically resolving the racemate. Such a process involving optical resolution of a racemate is uneconomical because an enantiomer having a configuration which is a mirror image of the desired optical isomer is discarded as unnecessary.
In recent years, many attempts have been directed to asymmetric syntheses. Proposals for asymmetric synthesis include, for example, asymmetric reduction of 3,4-dihydropapaverine as reported in H. B. Kagan et al., J. Organomet. Chem., Vol. 90, 353 (1975), asymmetric alkylation to tetrahydroisoquinoline as reported in A. I. Meyer et al., J. Am. Chem. Soc., Vol. 105, 117 (1983), and biosynthesis starting with an amino acid as reported in S. Yamada et al., Tetrahedron Letter, No. 22, 2215 (1972). However, any of these processes involve complicated steps and are not satisfactory for the production on an industrial scale.
Accordingly, it has been keenly demanded to establish a process which does not require complicated operations and directly provides an optical isomer of interest with high efficiency.